[18F]FEAC and [18F]FEDAC: Two novel positron emission tomography ligands for peripheral-type benzodiazepine receptor in the brain

Article abstract of DOI:10.1016/j.bmcl.2009.01.093

[¹⁸F]FEAC ([¹⁸F]4a) and [¹⁸F]FEDAC ([¹⁸F]4b) were developed as two novel positron emission tomography (PET) ligands for peripheral-type benzodiazepine receptor (PBR). [¹⁸F]4a and [¹⁸F]4b we

Full text of DOI:10.1016/j.bmcl.2009.01.093

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1707–1710
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Bioorganic & Medicinal Chemistry Letters
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[18F]FEAC and [18F]FEDAC: Two novel positron emission tomography ligands
for peripheral-type benzodiazepine receptor in the brain
Kazuhiko Yanamoto, Katsushi Kumata, Tomoteru Yamasaki, Chika Odawara, Kazunori Kawamura,
*
Joji Yui, Akiko Hatori, Kazutoshi Suzuki, Ming-Rong Zhang
Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
a r t i c l e i n f o
a b s t r a c t
18F]FEAC ([18F]4a) and [18F]FEDAC ([18F]4b) were developed as two novel positron emission tomography
Article history:
[
(PET) ligands for peripheral-type benzodiazepine receptor (PBR). [18F]4a and [18F]4b were synthesized by
fluoroethylation of precursors 8a and 8b with [18F]FCH2CH2Br ([18F]9), respectively. Small-animal PET
scan for a neuroinflammatory rat model showed that the two radioligands had high uptakes of radioac-
tivity in the kainic acid-infused striatum, a brain region where PBR density was increased.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 December 2008
Revised 26 January 2009
Accepted 28 January 2009
Available online 31 January 2009
Keywords:
Positron emission tomography
Fluorine-18
Peripheral-type benzodiazepine receptor
[18F]FEAC
[18F]FEDAC
The peripheral-type benzodiazepine receptor (PBR), which was
initially identified in the peripheral organs, including the kidney,
nasal epithelium, lung, heart, and endocrine organs, such as the
adrenal, testis, and pituitary gland,1–3 was subsequently found in
the central nervous system (CNS). In the CNS, PBR is mainly located
in glial cells, and PBR density was increased in glial cells activated
by brain injury and neuroinflammation.4 Many studies have
documented the relationship between PBR and brain injury or
neuroinflammation in experimental animals and in human neuro-
degenerative diseases, such as Alzheimer’s disease,5 Huntington’s
disease,6 multiple sclerosis,7 and stroke-induced brain injury.8
These results have prompted the development of positron emis-
sion tomography (PET) ligands labeled by positron-emitting radio-
isotopes, which has made it possible to visualize the distribution of
PBR in the animal and human brain.
higher in vivo specific binding to PBR in rodent and primate brains
than [11C]1, these ligands are being used for the clinical imaging of
PBR in the human brain. However, these PET ligands display
slow clearance from the brain, which requires time to reach equi-
librium and to gain maximum specific binding. Thus, PET studies
with these ligands are not simple to perform the quantitative
analysis.16,17
Here, using 3 as a lead compound, we designed three novel fluo-
rinated ligands: FEAC (4a, Scheme 1), FEDAC (4b), and FAC (4c).
These compounds can be labeled with 18F as putative PET ligands
for PBR imaging. Since 18F has an advantage over 11C, with a longer
half-life (110 min vs 20 min) and lower positron energy (633 keV vs
960 keV), 18F is convenient for long-time storage and long-distance
transportation and could give higher quality images with higher
spatial resolution. More importantly, because the kinetics and
metabolism of some [18F]fluoroalkylated ligands were improved
[
11C]PK11195 ([11C]1, Scheme 1) was the first ligand used for
clinical PET imaging of PBR. However, [11C]1 has several limita-
tions, such as relatively low brain uptake,9 high nonspecific bind-
ing,10 high plasma protein binding,11 and too high lipophilicity.
To characterize PBR precisely using a PET ligand with advantages
over [11C]1, nearly 20 new ligands labeled with 11C or 18F for the
PBR study have been reported.12 Recently, we have successfully
over the corresponding [11C]methylated version,18 18F]4a–c could
[
be expected to display more rapid clearance of radioactivity from
the brain than [11C]3 as well as [11C]2a and [18F]2b.
In this paper, we report: (1) chemical synthesis and in vitro
binding affinity of 4a–c to PBR and central benzodiazepine
receptor (CBR); (2) radiosynthesis of [18F]4a–c; (3) uptake and
kinetics of [18F]4a and [18F]4b in the brain of a neuroinflamma-
tory rat model using small-animal PET. For comparison, PET scan
using [18F]2b was performed for the same rat model. The animal
experimental procedures were approved by the Animal Ethics
Committee of the National Institute of Radiological Sciences
(NIRS).
developed [11C]DAA1106 ([11C]2a),9,13 18F]FEDAA1106 ([18F]2b),14
[
and [11C]AC-5216 ([11C]3)15 as useful PET ligands for PBR imaging
(Scheme 1). As [11C]2a, [18F]2b, and [11C]3 have higher uptake and
* Corresponding author. Tel.: +81 43 206 4041; fax: +81 43 206 3261.
E-mail address: zhang@nirs.go.jp (M.-R. Zhang).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.093

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K. Yanamoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1707–1710
OCH3
H3C
O
O
F
N
O
N
OR
N
11CH3
Cl
11C]PK11195 ([11C]1)
[
[
11C]DAA1106 ([11C]2a): R=11CH3
[
18F]FEDAA1106 ([18F]2b): R= CH2CH218F
R1
Ph
Ph
N
N
O
O
N
N
N
O
O
R2
N
R
N
N
N
Ph
FEAC (4a): R1= CH2CH3, R2= CH2CH2F
18F]FEAC ([18F]4a): R1= CH2CH3, R2= CH2CH218F
FEDAC (4b): R1= CH3, R2= CH2CH2F
18F]FEDAC ([18F]4b): R1= CH3, R2= CH2CH218F
FAC (4c): R1= CH2CH2F, R2= CH3
18F]FAC ([18F]4c): R1= CH2CH218F, R2= CH3
N
Ph
[
AC-5216 (3): R= CH3
[
11C]AC-5216 ([11C]3): R= 11CH3
[
[
Scheme 1. Chemical structures of PET ligands for PBR.
R1
N
R1
N
R1
N
OH
Ph
Ph
Ph
NaOH
b
O
HN
H
O
HN
N
O
HN
N
O
O
O
a
EtO
N
EtO
N
HO
N
N
Ph
Ph
Ph
7a: R1= CH2CH3
7b: R1= CH3
7c: R1= H
5
6a: R1= CH2CH3
6b: R1= CH3
6c: R1= H
R1
N
Ph
O
O
(PhO)2P-N3
FCH2CH2Br (9)
4a: R1= CH2CH3, R2= CH2CH2F
4c: R1= CH2CH2F, R2= CH3
N
O
R2
N
c
d
N
FCH2CH2OTs
f
N
Ph
4b: R1= CH3, R2= CH2CH2F
8a: R1= CH2CH3, R2= H
8b: R1= CH3 , R2= H
8c: R1=R2= H
CH3I e
8d: R1= H, R2= CH3
8a, 8b or 8d
[
[
[
18F]4a: R1= CH2CH3, R2= CH2CH218F
18F]4b: R1= CH3, R2= CH2CH218F
18F]4c: R1= CH2CH218F, R2= CH3
BrCH2CH2OTf
K
18F
18FCH2CH2Br
18F]9
g
h
[
Scheme 2. Chemical synthesis and radiosynthesis. Reagents and conditions: (a) BOP reagent, Et3N, DMF, 30 °C, 3 h, 53% (6a), 73% (6b), 65% (6c); (b) 5 N NaOH, EtOH, 80 °C,
30 min, quant. (7a), 83% (7b), 92% (7c); (c) Et3 N, DMF, 100 °C, 6 h, 33% (8a), 42% (8b), 83% (8c); (d) NaH, DMF, 50 °C, 5 h, 57% (4a), 43% (4c); (e) K2CO3, DMF, 25 °C, 1 h, 97%
(8d); (f) K2CO3, DMF, 80 °C, 3 h, 53% (4b); (g) o-dichlorobenzene, 130 °C, 2 min, 57%; (h) 0.5 N NaOH, DMF, 90 °C, 15 min, 64% ([18F]4a), 69% ([18F]4b), 3.2% ([18F]4c).
The fluoroalkyl ligands 4a–c and precursors (8a, 8b, and 8d) for
radiosynthesis were synthesized according to the reaction
sequences delineated in Scheme 2. The glycine derivative (5)19
was coupled with benzylamines in the presence of BOP reagent
to give amides 6a–c, which were then hydrolyzed with NaOH to af-
ford carboloxyic acids 7a–c. Curtius rearrangement of 7a–c using
diphenylphosphinic azide produced 8a–c in high chemical yield.
The final desired products 4a and 4b were prepared by the reaction

K. Yanamoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1707–1710
1709
Table 1
of 8a and 8b with FCH2CH2Br (9) and FCH2CH2OTs in the presence
In vitro binding affinity and lipophilicity of PBR ligands
of K2CO3, respectively. Methylation of 8c with CH3I gave 8d, fol-
lowed by reaction with 9 to give 4c.
Ligand
Ki (nM)a
Lipophilicity
Radioligands [18F]4a–c were synthesized as shown in Scheme 2.
The labeling method was a two-step reaction sequence which in-
volved the preparation of the radioactive intermediate [18F]FCH2
CH2Br ([18F]9, bp: 71.5 °C), followed by the alkylation of 8a, 8b,
and 8d with [18F]9. Reagent [18F]9 was prepared by the reaction
of [18F]FÀ with TfOCH2CH2Br using an automated system devel-
oped in our institute.20 After the fluorinating reaction, [18F]9 was
distilled from the reaction mixture and trapped in a mixture of pre-
cursor and base to accomplish [18F]fluoroethylation. This purifica-
tion of [18F]9 by distillation was effective for radiosynthesis,
because this treatment left behind all non-volatile impurities such
as metal ions from the cyclotron target, unreacted [18F]FÀ and the
phase transfer reagent Kryptofix 222/K2CO3.
PBRb
CBRc
LogDd
cLogDe
4a
4b
4c
3
1
2b
FEAC
FEDAC
FAC
AC-5216
PK11195
FEDAA1106
0.49 0.05
1.34 0.15
0.51 0.06
0.20 0.02
0.31 0.03
0.08 0.01f
>8400
8400
>8400
>8400
>8400
>1000f
3.6
3.2
3.1
3.3
3.7
3.8f
3.6
3.3
3.3
3.5
5.1
4.3
a
Values are means SD determined in duplicate rat brain homogenates.
b
[
11C]1 was incubated in the presence of the ligands examined except for 2b.
[
11C]2a was used to measure the affinity of 2b.
c
[
11C]Flumazenil was incubated in the presence of the ligands examined.
LogD were determined in the octanol/phosphate buffer (pH 7.4) system by
d
shaking flash method.
e
The cLogD was calculated with Pallas 3.4 software (CompuDrug).
f
[
18F]fluroroethylation was performed by reacting 8a, b, and d
(0.8–1.2 mg, about 2.5 L) using
mol) with [18F]9 in DMF (300
NaOH (0.5 N, 6 L) as a base at 90 °C for 15 min, respectively.
Data from Ref. 14.
l
l
were potent and selective ligands for PBR, and had moderate
lipophilicity.
l
The radiochemical yield of [18F]4a–c was measured with analytic
HPLC (CAPCELL PAK C18 column: 4.6 mm ID Â 150 mm, CH3CN/
H2O: 60/40) based on the HPLC-injected radioactivity of each reac-
tion mixture. The yields of [18F]4a and [18F]4b were 64% and 69%,
whereas that of [18F]4c was less than 10%. To increase the [18F]flu-
oroethylating efficiency of 8d, in place of [18F]9, [18F]FCH2CH2I,
We determined the uptake (expressed as standardized uptake
value: SUV) and kinetics of [18F]4a and [18F]4b in the neuroinflam-
matory rat brain using a small-animal PET scanner, InveonTM (Sie-
mens Medical Solutions USA). As the normal rat brain has lower
PBR density than peripheral tissues, we used a kainicacid (KA)-le-
sioned rat with excess density of PBR in the brain for evaluation.4
[
18F]FCH2CH2OTs or [18F]FCH2CH2OTf21 was reacted with 8d and
To induce neuroinflammation, KA (5 nmol in PBS of 2 lL) was in-
NaH was used instead of NaOH; however, these treatments could
not augment the radiochemical yield of [18F]4c. The result sug-
gested that attachment of the fluoroethyl group to benzylamide
in 8d was difficult. The putatively rigid conformation of this amide,
which was assumed from the NMR data (4.87 ppm, d, J = 19.1 Hz,
2H) corresponding to methylene of benzyl in 8d, could not provide
enough space for the approach of [18F]9.
fused into the right striatum of male SD rats (9 weeks old). PET
scans were performed at 8–10 days after KA infusion. To examine
whether the kinetics of these ligands were improved, we also per-
formed the PET scan using [18F]2b.14 Because the radiochemical
yield of [18F]4c was too low, the PET scan using [18F]4c was not
performed this time.
The brain kinetics of [18F]4a, [18F]4b, and [18F]2b are shown in
Figure 1. These ligands entered the brain rapidly and the radioac-
tivity level peaked within 1–3 min after injection. Higher uptake
of these ligands was observed in the lesioned striatum than in
the non-lesioned striatum. This result suggested that the increased
binding of these ligands was caused by overexpression of PBR in
the rat brain with neuroinflammation. The kinetics of [18F]4a and
Purification of the reaction mixtures using reversed phase semi-
preparative HPLC (CAPCELL PAK C18 column: 4.6 mm ID Â 250 mm,
CH3CN/H2O: 60/40) gave the desired radioactive products [18F]4a–
c in 35 10% (n = 4), 46 9% (n = 4) and <3% radiochemical yield
based on the total [18F]FÀ, corrected for physical decay in a synthe-
sis time of 45 2 min from the end of bombardment, respectively.
The identity of these radioactive products was confirmed by co-
injection with the corresponding non-radioactive 4a–c on analytic
HPLC. In the final product solutions, the radiochemical purity of
[
18F]4b differed from that of [18F]2b. [18F]4a and [18F]4b exhibited
relatively rapid clearance in the lesioned and non-lesioned stria-
tum. In contrast, [18F]2b showed little clearance in the lesioned
striatum. The maximum SUV in the lesioned and non-lesioned stri-
atum was about 1.2 and 0.8 ([18F]4a), 1.6 and 0.9 ([18F]4b), and 1.5
and 1.3 ([18F]2b), respectively. The radioactivity level of these li-
gands was similar to or higher than those of two PBR-selective li-
gands ([11C]DPA-713, [11C]CLINME) in the neuroinflammatory rat
brain.22,23
[
18F]4a–c was higher than 98% and the specific activity was 30–
95 GBq/ mol. No significant UV peak corresponding to 8a, 8b,
l
and 8d and other chemical impurities was observed on HPLC charts
of the final products. Moreover, the radiochemical purity of
[
18F]4a–c remained >95% after 180 min at 25 °C, and these ligands
were stable for the time of a PET scan.
The in vitro binding affinities (Ki) of 4a–c for PBR were deter-
mined from competition for the [11C]1 binding to PBR using rat
brain homogenate. As shown in Table 1, 4a showed high affinity
for PBR, although its potency was slightly weaker than that of 1
and 3. This result suggested that substituting N-CH3 with the N-
CH2CH2F group in the purine moiety did not have a significant ef-
fect on the affinity for PBR. Substitution of N-CH2CH3 of the amide
moiety (4a) by the N-CH3 group (4b) weakened the affinity for
PBR, indicating that this replacement might have a negative influ-
ence on the binding affinity. Introduction of a fluorine atom (4c)
to the CH2CH3 group (3) induced a slight decrease in the affinity,
which might be slightly due to the mimic effect of fluorine on the
hydrogen atom. The affinity of 4a–c for CBR was measured using
[
18F]4a and [18F]4b displayed the maximum ratio (2.5–3.0) of
radioactivity between lesioned and non-lesioned striatum within
10–20 min, whereas [18F]2b displayed the maximum (1.5) at
60 min until the end of the PET scan. The ratios of [18F]4a and
[
18F]4b were about 2-fold higher than that of [18F]2b. Moreover,
the time required to achieve the maximum ratio of [18F]4a and
18F]4b was earlier than that of [18F]2b. From these results, the
[
kinetics of [18F]4a and [18F]4b were more favorable for quantitative
analysis to elucidate receptor density and occupancy, and to rap-
idly gain a high ratio of radioactivity between lesioned and non-le-
sioned sides. The improved kinetics of [18F]4a and [18F]4b may be
mainly attributed to the suitable binding affinity for PBR. The affin-
ity of [18F]2b may be too high, so it is difficult to dissociate from
PBR in the brain. The higher lipophilicity of [18F]2b may also be re-
lated to its slow kinetics.
[
11C]flumazenil, as shown in Table 1. These ligands did not show
significant inhibitory effects (Ki > 1 M) on
11C]flumazenil
l
[
binding in the rat brain homogenate. As shown in Table 1, the
lipophilicity of these ligands was decreased in the following or-
der: 1, 2b > 4a > 3, 4b, and 4c. These results revealed that 4a–c
In conclusion, we synthesized and evaluated [18F]4a and [18F]4b
as potent ligands for PBR using small-animal PET and neuroinflam-

1710
K. Yanamoto et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1707–1710
(A) [18F]4a
(B) [18F]4b
(C) [18F]2b
2.0
1.5
1.0
0.5
0.0
2.0
1.5
1.0
0.5
0.0
2.0
1.5
1.0
0.5
0.0
Lesioned Striatum
Non-Lesioned Striatum
0
10 20 30 40 50 60
Time (min)
0
10 20 30 40 50 60
Time (min)
0
10 20 30 40 50 60
Time (min)
Figure 1. Time-activity curves for [18F]4a (A, n = 4), [18F]4b (B, n = 4), and [18F]2b (C, n = 2) in lesioned (filled circles) and non-lesioned (open circles) striatum of
neuroinflammatory rats. Brain uptake of radioactivity was expressed as the standardized uptake value (SUV), normalized for injected radioactivity and body weight.
SUV = (radioactivity per cubic centimeter tissue/injected radioactivity) Â gram body weight. The results are means SD.
matory rats. [18F]4a and [18F]4b have potent binding affinity and
selectivity for PBR, high signal to neuroinflammation, and rapid
7. Debruyne, J. C.; Versijpt, J.; Van Laere, K. J.; De Vos, F.; Keppens, J.; Strijckmans,
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kinetics in the brain. Therefore, they are promising PET ligands for
PBR imaging and could be better in detecting smaller changes in
PBR expression than [18F]2b. Further investigation into the binding
of [18F]4a and [18F]4b to PBR in the primate brain is currently
underway.
8. Rojas, S.; Martín, A.; Arranz, M. J.; Pareto, D.; Purroy, J.; Verdaguer, E.; Llop, J.;
Gómez, V.; Gispert, J. D.; Millán, O.; Chamorro, A.; Planas, A. M. J. Cereb. Blood
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12. Chauveau, F.; Boutin, H.; Van Camp, N.; Dollé, F.; Tavitian, B. Eur. J. Nucl. Med.
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We are grateful to Mrs. M. Takei (Tokyo Nuclear Service Co., Ltd.),
K. Minegishi (Neos Tech Co., Ltd.) for technical support with radio-
synthesis. This study was supported in part by Grants-in-Aid for
Scientific Research (Basic Research C: Zhang, M.-R., 19590114) and
for the Molecular Imaging Program from the Ministry of Education,
Culture, Sports, Science and Technology, Japanese Government.
16. Fujimura, Y.; Ikoma, Y.; Yasuno, F.; Suhara, T.; Ota, M.; Matsumoto, R.; Nozaki,
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Supplementary data
17. Ikoma, Y.; Yasuno, F.; Ito, H.; Suhara, T.; Ota, M.; Toyama, H.; Fujimura, Y.;
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.01.093.
19. Murata, A.; Masumoto, K.; Kondo, K.; Furukawa, K.; Oka, M. inventors;
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